Mutation Notes

Quiz Announcement

  • Quiz this week on the 13th (Sunday).
  • Short writing assignment related to mutation and previous topics.
  • Be comprehensive and succinct in your answer.

Introduction to Mutations

  • Continuing discussion on mutations and their effects on polypeptide chains.
  • Focus on changes to DNA or RNA strands and their downstream consequences.
  • Emphasis on how changes affect gene products.
  • Today's focus: single point mutations.
  • Wednesday's focus: Larger changes and their effects.

Definition of Mutations

  • Mutations: Changes from the original DNA form.
  • Can result in altered proteins due to DNA-RNA-polypeptide chain connection.
  • Examples:
    • Flower color changes.
    • Domestication of animals (e.g., longhorn to shorthorn cows).
    • Mendel's pea traits (round vs. wrinkled peas - protein variation).
    • Fruit fly color (normal vs. yellow) due to single protein change.

DNA Characteristics for Mutation

  • Mutation must occur in a gene to affect phenotype.
  • DNA must store all genetic material.
  • DNA must be mutable.
  • DNA must be replicable to maintain mutations in a population.
    • Examples: Glow-in-the-dark fish and mice (scientifically modified mutations).

Structure-Function Relationship of Proteins

  • Structure dictates function.
  • Protein structure is determined by amino acid sequence and interactions.
  • Changing a single amino acid can drastically alter protein structure.
    • Example: Changing a cysteine involved in a disulfide bond can prevent proper folding.
  • Normal folded protein vs. misfolded protein due to a single change.

Types of Point Mutations

  • Point mutations: Focus of today's lecture.
  • Types:
    • Substitutions.
    • Insertions.
    • Deletions.
    • Functional mutations.

Transitions and Transversions

  • Single base changes within DNA.
  • Transition: Purine to purine or pyrimidine to pyrimidine.
    • Purines: Adenine (A) and Guanine (G).
    • Pyrimidines: Thymine (T) and Cytosine (C).
    • Examples:
      • A to G or G to A.
      • T to C or C to T.
  • Transversion: Purine to pyrimidine or pyrimidine to purine.
    • Examples:
      • A to T or A to C.
      • G to T or G to C.
      • C to A or C to G.
      • T to A or T to G.
  • Mnemonic Device: Circle with A & G across from each other (top/bottom) and T & C on the sides.
    • Transitions: Go straight across the circle (A to G, T to C).
    • Transversions: Go sideways (A to T/C, G to T/C).
  • Transitions/transversions differentiate species and build phylogenetic trees.

Frequency of Transitions vs. Transversions

  • Transitions occur more frequently.
  • Reason: Transitions involve similar base structures, whereas transversions require changing the base structure (single vs. double aromatic rings).
  • Chemical changes are easier in trnasitions.

Insertions and Deletions (Single Base)

  • Silent Mutations:
    • DNA changes, but no change in amino acid sequence due to the degeneracy of the genetic code where multiple codons code for the same amino acid.
    • Example: Change in the third position of a codon (wobble).
    • Analogy: "The cat saw the dog hit the can" vs. "The cat saw the dog hit the can" (capitalization change).
  • Missense Mutations:
    • Change in nucleotide sequence results in a different amino acid.
    • Changing the first position of a codon almost always changes the amino acid.
    • Severity depends on the importance of the amino acid.
    • Analogy: “The cat saw the dog hit the can” becomes “The bat saw the dog hit the king”.
    • Example:
      • Sickle cell anemia: Single base mutation changes glutamic acid to valine.
  • Nonsense Mutations:
    • Mutation creates a stop codon.
    • Results in a truncated protein.
    • Severity depends on where the stop codon occurs.
    • Example: Cystic fibrosis and muscular dystrophy, often has caused by stop codons.
    • Analogy: "The cat saw the dog…" (everything after the stop codon is missing).

Frameshift Mutations

  • Gain or loss of nucleotides, altering the reading frame.
  • Changes all amino acids after the mutation.
  • Analogy: "The cat saw the dog hit the can" with a single base deletion becomes nonsensical.
  • Severity depends on the location of the change and the importance of affected amino acids.
  • Example: Crohn's disease is caused by frame shift in NOD2 gene.
  • Insertion of a nucleotide can also cause a frame shift and lead to a premature stop codon.

In-Frame Mutations

  • These are in frame mutations and it's not just a single base.
  • Loss of entire codons. In this case, what if we lose UCA?
  • Loss of a codon means loss of an amino acid.
  • Analogy: Losing "saw" in “The cat saw the dog hit the can” changes the meaning.
  • How severe is that?
  • Loss of multiple codons can significantly alter the protein.

Functional Mutations

  • Change the function of a protein.
  • Loss of Function (Amorphic):
    • Complete loss of gene function.
  • Gain of Function (Neomorphic):
    • New function for the protein.
  • Not all mutations are bad.

Lethal Mutations

  • Lead to death.
  • Premature stop codons, missense mutations, or frame shifts, can be mutations

Location of Mutations

  • Somatic Cells (Non-Sex Cells):.
    • Not passed down to offspring.
    • Often induced by carcinogens.
    • Examples: Lung cancer (smoking), skin cancer (UV radiation).
  • Germ Cells (Sex Cells):.
    • Passed down to offspring.
    • Typically more severe.
    • Example: Hemophilia.

Mechanisms Causing Mutations

  • Spontaneous mutations.
  • Induced mutations.

Spontaneous Mutations During Replication

  • Occur during the replication process.
  • High fidelity needed: Each time cells replicate they need to copy 3,000,000,000, and making that an exact copy winds up being 6,000,000,0006,000,000,000
  • Mutation rate: One error per 100,000 bases.
  • Approximately 20,000 errors per cell division.

Replication Errors and Non-Watson-Crick Base Pairing

  • Non-Watson-Crick base pairing: Thymine-guanine or cytosine-adenine interactions.
  • Caused by forcing incorrect pairs together due to surrounding base pairing.

Strand Slippage

  • Occurs in microsatellites or long stretches of the same base.
  • DNA polymerase loses its place on the strand.
  • Polymerase slips forward, causing the parental strand to bulge, leading to fewer bases.
    *Gar Streisinger discovered this.

Chemical Changes

  • Depurination: Loss of a purine (A or G), resulting in an apurinic site.
  • Deamination: Loss of an amine group.
    • Cytosine can be deaminated to uracil.
    • 5-methylcytosine can be deaminated to thymine, which results in mutations.